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《工程(英文)》 >> 2021年 第7卷 第11期 doi: 10.1016/j.eng.2020.11.013

靶向膜蛋白的抗体药物开发的新进展

a Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
b Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou 215123, China
c Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou 215123, China
d Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliation Hospital of Soochow University, Suzhou 215123, China
e State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, China

收稿日期: 2020-02-10 修回日期: 2020-08-21 录用日期: 2020-11-16 发布日期: 2021-09-30

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摘要

在疾病干预的众多膜蛋白靶标中,G蛋白偶联受体(GPCR)作为人体内最大的膜受体蛋白家族,成为很多药物的重要靶点,其次是离子通道、转运蛋白和激酶等。膜蛋白在细胞信号转导和运输中发挥了关键作用,当前药物研发面临的挑战在于进一步发掘此类膜蛋白的潜在靶点的干预价值,开发治疗性抗体药物。鉴于特异性抗体能够识别膜蛋白的灵敏特性,以及随着基因工程技术的进步,对已有抗体进行加工改造可获得适应多个靶点蛋白的特异性抗体。然而,成功分离特异靶向膜蛋白抗体取决于一系列因素。我们更易研制和识别结构简单且具有长片段胞外区的抗体分子,但对于高难度的靶点蛋白,如GPCR和其他复杂膜蛋白往往难以得到具有活性的候选抗体。目前若要开发针对复杂膜蛋白(如GPCR、离子通道、转运蛋白和激酶)的抗体药物,必须从抗原靶点设计、抗体筛选策略、先导抗体优化及药物研发模式方面进行考虑。深入研究靶标膜蛋白的结构有助于推进治疗性抗体药物的开发进程。本文概述了抗体靶向复杂膜蛋白的优势和挑战,以及膜蛋白抗原制备和抗体研发策略的最新进展。

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